From the Guidelines
When evaluating testosterone deficiency, it is crucial to consider both total and free testosterone measurements, with free testosterone being more clinically relevant, especially in conditions like obesity, where binding proteins may be altered, as indicated by 1.
Key Differences Between Total and Free Testosterone
- Total testosterone measures all testosterone in the blood, including testosterone bound to proteins (sex hormone-binding globulin and albumin) plus the unbound or "free" testosterone.
- Free testosterone, which typically represents only 1-4% of total testosterone, is the biologically active form that can enter cells and exert hormonal effects.
Clinical Relevance
- Free testosterone is often more clinically relevant, especially in conditions where binding proteins may be altered, such as obesity, liver disease, or thyroid disorders, which can affect total testosterone levels without necessarily changing the amount of bioavailable hormone, as noted in 1.
- The combination of low testosterone levels and clinical symptoms such as decreased libido, erectile dysfunction, fatigue, and reduced muscle mass provides the most reliable basis for diagnosis and treatment decisions, according to 1.
Diagnosis and Evaluation
- For diagnosis, morning samples (between 8-10 AM) should be collected when testosterone levels are highest, and abnormal results should be confirmed with a second measurement, as recommended by 1.
- Normal reference ranges vary by laboratory but generally fall between 300-1000 ng/dL for total testosterone and 5-21 ng/dL for free testosterone in adult males.
Importance of Accurate Diagnosis
- Accurate diagnosis of testosterone deficiency is essential to guide treatment decisions and improve patient outcomes, as emphasized in 1.
- Clinicians should consider measuring total testosterone in patients with a history of unexplained anemia, bone density loss, diabetes, exposure to chemotherapy, exposure to testicular radiation, HIV/AIDS, chronic narcotic use, male infertility, pituitary dysfunction, and chronic corticosteroid use, even in the absence of symptoms or signs associated with testosterone deficiency, as suggested by 1.
From the FDA Drug Label
Testosterone in plasma is 98 percent bound to a specific testosterone-estradiol binding globulin, and about 2 percent is free. Generally, the amount of this sex-hormone binding globulin in the plasma will determine the distribution of testosterone between free and bound forms, and the free testosterone concentration will determine its half-life
The main difference between total and free testosterone is the binding state of the hormone in the blood.
- Total testosterone refers to the total amount of testosterone present in the blood, including both bound and free fractions.
- Free testosterone refers to the small percentage (about 2%) of testosterone that is not bound to any proteins in the blood and is available to enter cells and exert its effects. The bound fraction of testosterone is attached to a specific protein called sex-hormone binding globulin (SHBG) and is not available to enter cells. The distribution of testosterone between free and bound forms is determined by the amount of SHBG in the plasma 2.
From the Research
Difference between Total and Free Testosterone
- Total testosterone refers to the total amount of testosterone present in the blood, including both bound and free testosterone 3.
- Free testosterone, on the other hand, refers to the amount of testosterone that is not bound to proteins in the blood and is available to enter cells and perform its functions 3.
- Most testosterone circulates tightly bound to sex hormone-binding globulin (SHBG) or weakly bound to albumin, with only a minor amount circulating as free testosterone 3.
Clinical Utility of Free Testosterone Measurement
- Measurement of free testosterone is important in the diagnosis of many diseases, including disorders of androgen deficiency in men (i.e., hypogonadism) and androgen excess in women (i.e., polycystic ovary syndrome and hirsutism) 3.
- Free testosterone measurement can be useful in evaluating testosterone deficiency, especially in men with alterations in binding protein concentrations or in whom total testosterone levels are only slightly above or slightly below the normal range [(4,5)].
Methods of Measuring Free Testosterone
- Several methods are available for measuring free testosterone, including equilibrium dialysis, ultrafiltration, analog immunoassay, and calculated free testosterone based on measurement of total testosterone, SHBG, and albumin 3.
- The gold standard equilibrium dialysis method is too complex for use in routine clinical laboratories, and assays are not harmonized, making it challenging to interpret results 4.
- Calculated free testosterone may offer the best way forward, but better equations are needed to improve accuracy, and these should be derived from detailed knowledge of testosterone binding to SHBG 4.
Importance of Accurate Measurement
- Accurate measurement of total and free testosterone levels is essential for making the diagnosis of androgen disorders [(6,5)].
- Total testosterone should ideally be measured in a fasting state in the morning using a reliable assay, such as liquid chromatography tandem mass spectrometry, in a laboratory that is certified by an accuracy-based benchmark [(6,5)].
- Free testosterone levels should be measured in men in whom alterations in binding protein concentrations are suspected or in whom total testosterone levels are only slightly above or slightly below the lower limit of the normal male range for testosterone 5.